This invention relates to compositions and methods capable of detecting cancer cells or malignant tumors in humans. More particularly, this invention relates to compositions radio-labeled with Tc-99m which, when administered to a human, will accumulate at tumor sites producing a) human chorionic gonadotropin (hCG), hCG alpha subunit, hCG beta subunit or an hCG-like material or b) any other tumor associated antigen to which an antibody molecule can be prepared to include carcinoembryonic antigen (CEA) or the like.
The use of compositions which emit radiation at levels which can be detected after administration to the human body are well known. These compositions are utilized to visualize and/or monitor the functioning of various parts of the body or are used diagnostically to determine the absence or presence of particular tissue damage or disease. In one particular aspect of the prior art, radiolabeled antibodies are utilized to detect tumors having associated therewith carcinoembryonic antigen (CEA). As disclosed in U.S. Pats. Nos. 3,663,684, 3,867,363 and 3,927,193, I.sup.131 or I.sup.125 labeled antibodies to CEA are utilized to detect tumors which produce or are associated with CEA.
It is also well known that protein molecules can be tagged with Tc-99m in order to form diagnostic agents. An example of such a composition is Tc-99m labeled human serum albumin. The use of chelating agents for the radiolabeling of protein molecules with transition metals such as In-111 and/or Tc-99m has also been described (Meares et al, Proc. Nat. Acad. Sci., U.S.A., Vol. 11, pp 3803-3806, 1976). In addition, the use of a chelating agent for the radiolabeling of antibodies and antibody fragments including F (ab').sub.2 and Fab fragments reactive with human myosin has been described as potentially useful for imaging of myocardial infarction (Khaw and Haber, "Radioimmunochemical imaging of myocardial infarction: Utilization of anticardiac myosin antibodies." In: Tumor Imaging: The Radioimmunochemical Detection of Cancer, Ed. Burchiel, S.W., et al, U.S.A. (New York) in press.)
It has also been proposed to tag the antibody with peroxidase (McManus et al., Cancer Research, 36. pp. 2367-3481, September, 1976) in order to localize the antigen in malignant tumors in vitro. Furthermore, it has been proposed to label the IgG antibody to hCG with radioactive iodine in order to localize the antigen in human choriocarcinomas transplanted in hamster cheek pouches (Quinones et al, 1971, Journal of Nuclear Medicine, Vol. 12, pp. 69-75.) Also, it is known to utilize anti-hCG labeled with tritium or iodine to test for cancer in a human using an in vitro diagnostic test, (U.S. Pat. No. 4,116,776, Dalbow et al.)
Recently, it has been found that neoplastic tissues produce and/or express on their surface chorionic gonadotropin, chorionic gonadotropin-like material, compounds similar to and/or identical to the alpha-chain or beta-chain of chorionic gonadotropin or mixtures thereof, specifically to the degree where it is considered a more general marker than either carcinoembryonic antigen (CEA) or alphafetoprotein (AFP), (Acevedo et al., "Detection and Prevention of Cancer", Part 2, Vol. I, H. E. Nieburgs (ED) Marcel Dekker, Inc., New York, 1978, pp. 937-979). The positive identification of chorionic gonadotropin in a heterogenous group of cancer cells and its non-detection in non-cancer cells in vitro has suggested to these authors that the compound is a common antigen (common denominator) of every cell with oncogenic properties.
While rediolabeled IgG antibodies are useful for localizing tumors in vivo, when a radioisotope of sufficient half-life is present, the IgG antibodies comprise the immunoglobulins which tend to stay in the blood stream for many hours following intravenous administration. This increases the difficulty in imaging the tumor within a reasonable time period, since blood levels of the labeled IgG antibodies maintain a relatively high background activity. In nuclear medicine, a high ratio of target (tumor) to background emission is desired to obtain an image of sufficient quality to permit detection. With short-lived radioisotopes, such as Tc99m (6 hour half-life), it becomes difficult to image without the use of sophisticated background subtraction techniques (Goldenberg et al., New Eng. J. Med., Vol. 298, pp 1384-1388, 1978).
In previous published studies, it has also been shown that radioiodinated IgG antibodies specific to digoxin have a prolonged half-life in the blood stream of rabbits and baboons compared to radioiodinated Fab fragments of the same antibody (Smith et al, Clin. Exp. Immunol., 36, 384-396, 1979). In these experiments, Fab fragments of anti-digoxin antibodies were tested to determine whether the antibody fragments had a different biodistribution pattern than the whole IgG molecule following intravenous administration, and whether the Fab fragments were less toxic than IgG.